Rationale and study protocol for the BRITISH randomized trial (Using cardiovascular magnetic resonance identified scar as the benchmark risk indication tool for implantable cardioverter defibrillators in patients with nonischemic cardiomyopathy and severe systolic heart failure).

BACKGROUND: For patients with nonischemic cardiomyopathy (NICM), current guidelines recommend implantable cardioverter defibrillators (ICD) when left ventricular ejection fraction (LVEF) is ≤35%, but the DANISH trial failed to confirm that ICDs reduced all-cause mortality for such patients. Circumstantial evidence suggests that scar on CMR is predictive of sudden and arrhythmic death in this population. The presence of myocardial scar identified by cardiac magnetic resonance imaging (CMR) in patients with NICM and an LVEF ≤35% might identify patients at higher risk of sudden arrhythmic death, for whom an ICD is more likely to reduce all-cause mortality. METHODS/DESIGN: The BRITISH trial is a prospective, multicenter, randomized controlled trial aiming to enrol 1,252 patients with NICM and an LVEF ≤35%. Patients with a nonischemic scar on CMR will be randomized to either: (1) ICD, with or without cardiac resynchronization (CRT-D), or (2) implantable loop recorder (ILR) or cardiac resynchronization (CRT-P). Patients who are screened for the trial but are found not to be eligible, predominantly due to an absence of scar or those who decline to be randomized will be enrolled in an observational registry. The primary endpoint is all-cause mortality, which we plan to assess at 3 years after the last participant is randomized. Secondary endpoints include clinical outcomes, appropriate and inappropriate device therapies, symptom severity and well-being, device-related complications, and analysis of the primary endpoint by subgroups with other risk markers. CONCLUSION: The BRITISH trial will assess whether the use of CMR-defined scar to direct ICD implantation in patients with NICM and an LVEF ≤35% is associated with a reduction in mortality.

Managing Parkinson's during the COVID-19 pandemic: Perspectives from people living with Parkinson's and health professionals.

OBJECTIVES: The aim of this study was to understand how people living with Parkinson's and healthcare professionals perceived their care management and interactions with health services were affected during the COVID-19 pandemic. BACKGROUND: During the COVID-19 pandemic, many governments introduced restrictions and services that support Parkinson's care management had to cease or be delivered remotely. These changes may have had an impact on the well-being of people living with Parkinson's. METHODS: A qualitative exploratory UK study was carried out. Semi-structured individual interviews with people living with Parkinson's and health professionals were recorded, transcribed verbatim and analysed using Braun´s and Clarke´s thematic analysis. Eleven patients and 10 health professionals were recruited between April and September 2020. The study was reported using the COREQ. RESULTS: Two main themes were identified. In the first theme, many patients and professionals reported that the COVID-19 pandemic made some people living with Parkinson's feel isolated and vulnerable due to disruptions to their social networks and usual activities related to Parkinson's disease care. However, other patients remained connected with their networks. In the second theme, patients and most professionals mentioned that some clinical practices were cancelled, delayed or transformed to remote consultation. CONCLUSION: The COVID-19 restrictions had an impact on how people living with Parkinson's managed their care and in their interactions with healthcare services. Health professionals should assess the risk of vulnerability, social isolation, physical inactivity and confidence with remote consultations in people living with Parkinson's. This might inform a rethinking of existing clinical interactions with people living with Parkinson's towards a flexible, sustainable, person-centred care model. RELEVANCE TO CLINICAL PRACTICE: This study has shown that Parkinson's care management and interactions with healthcare services should provide personalised and flexible support. To meet this challenge, the design of the organisation of health services should include greater involvement of patients and person-centred care models.

Pharmacokinetics of ß-d-N4-Hydroxycytidine, the Parent Nucleoside of Prodrug Molnupiravir, in Nonplasma Compartments of Patients With Severe Acute Respiratory Syndrome Coronavirus 2 Infection.

ß-d-N4-hydroxycytidine (NHC), the parent nucleoside of molnupiravir, a COVID-19 antiviral, was quantified at SARS-CoV-2 transmission sites in 12 patients enrolled in AGILE Candidate-Specific Trial-2. Saliva, nasal, and tear NHC concentrations were 3%, 21%, and 22% that of plasma. Saliva and nasal NHC were significantly correlated with plasma (P < .0001). Clinical Trials Registration. NCT04746183.

ELEVATE - evaluating Temozolomide and Nivolumab in patients with advanced unresectable previously treated oesophagogastric adenocarcinoma with MGMT methylation: study protocol for a single arm phase II trial.

BACKGROUND: For patients with oesophagogastric adenocarcinoma, surgery is the only curative option and despite the use of multimodality therapy, which combines it with chemotherapy and/or radiotherapy, more than 50% of patients will relapse and die. Many UK patients present with advanced disease which is already inoperable or metastatic at diagnosis. For these patients, standard care chemotherapy only offers them survival of less than a year. Nivolumab, a checkpoint blockade inhibitor, has been found to work in some advanced cancers. It is proposed, for those where immunotherapy hasn't worked, that these immunologically evasive tumours need to be sensitized to immunotherapy drugs to allow them to act. METHODS: ELEVATE is a single arm phase II trial testing the overall response to nivolumab following temozolomide treatment in patients with advanced unresectable previously treated adenocarcinoma which is O6-methylguanine-DNA-methyltransferase (MGMT) methylated. 18 patients are being recruited from UK secondary care sites. To be eligible, participants must have been treated with at least 3 months of platinum and fluoropyrimidine chemotherapy. Participants will receive 50 mg/m2 temozolomide continuously for 3 months. If their disease progresses during the 3 months, they will stop temozolomide and start nivolumab at a dose of 240mg every 2 weeks. If there is no progression after 3 months the participant will continue taking temozolomide in combination with nivolumab. All treatment will stop once the participant progresses on nivolumab. The primary endpoint is the best overall response to nivolumab, using both Response Evaluation Criteria in Solid Tumours version 1.1 and immunotherapy modified Response Evaluation Criteria in Solid Tumours. Secondary endpoints include progression-free survival, overall survival, and quality of life. DISCUSSION: ELEVATE will provide evidence for whether giving nivolumab after temozolomide in patients with previously treated advanced oesophagogastric adenocarcinoma is safe and biologically effective prior to future randomised trials. TRIAL REGISTRATIONS: EudraCT Number: 2020-004771-41 (issued 01 October 2020); ISCRTN11398887 (registered 14 July 2021).

Practical recommendations for implementing a Bayesian adaptive phase I design during a pandemic.

BACKGROUND: Modern designs for dose-finding studies (e.g., model-based designs such as continual reassessment method) have been shown to substantially improve the ability to determine a suitable dose for efficacy testing when compared to traditional designs such as the 3 + 3 design. However, implementing such designs requires time and specialist knowledge. METHODS: We present a practical approach to developing a model-based design to help support uptake of these methods; in particular, we lay out how to derive the necessary parameters and who should input, and when, to these decisions. Designing a model-based, dose-finding trial is demonstrated using a treatment within the AGILE platform trial, a phase I/II adaptive design for novel COVID-19 treatments. RESULTS: We present discussion of the practical delivery of AGILE, covering what information was found to support principled decision making by the Safety Review Committee, and what could be contained within a statistical analysis plan. We also discuss additional challenges we encountered in the study and discuss more generally what (unplanned) adaptations may be acceptable (or not) in studies using model-based designs. CONCLUSIONS: This example demonstrates both how to design and deliver an adaptive dose-finding trial in order to support uptake of these methods.

Influence of social networks on cancer survivors' self-management support: A mixed methods study.

OBJECTIVE: The role of social networks, especially weaker ties (e.g. casual acquaintances and hobby groups), in self-management of long-term consequences of cancer is unexplored. This study aimed to explore the structure of cancer survivors' social networks and their contribution to self-management support and health-related quality of life (HRQoL). METHODS: The study used a sequential, exploratory mixed methods design. Phase 1 surveyed 349 lymphoma, colorectal, breast and prostate cancer survivors. Phase 2 analysed 20 semi-structured interviews with respondents recruited from Phase 1. RESULTS: Phase 1 results suggested participants' HRQoL increased if they participated in an exercise group, if their self-management skills increased, and social distress and negative illness perception decreased (p < 0.0005 adj. R2 = 0.631). These findings were explored in Phase 2, identifying underlying mechanisms. Four themes were identified: disrupted networks after cancer treatment; navigating formal support and building individual capacity; peer networks and self-management knowledge and linking networks to enable adaptation in recovery. CONCLUSIONS: This study suggests engagement with community groups, particularly those not directly related to illness management and social interaction with weak ties, make a valuable contribution to self-management support, increase HRQoL and enhance well-being.

Nivolumab versus placebo in patients with relapsed malignant mesothelioma (CONFIRM): a multicentre, double-blind, randomised, phase 3 trial.

BACKGROUND: No phase 3 trial has yet shown improved survival for patients with pleural or peritoneal malignant mesothelioma who have progressed following platinum-based chemotherapy. The aim of this study was to assess the efficacy and safety of nivolumab, an anti-PD-1 antibody, in these patients. METHODS: This was a multicentre, placebo-controlled, double-blind, parallel group, randomised, phase 3 trial done in 24 hospitals in the UK. Adult patients (aged ≥18 years) with an Eastern Cooperative Oncology Group performance status of 0 or 1, with histologically confirmed pleural or peritoneal mesothelioma, who had received previous first-line platinum-based chemotherapy and had radiological evidence of disease progression, were randomly assigned (2:1) to receive nivolumab at a flat dose of 240 mg every 2 weeks over 30 min intravenously or placebo until disease progression or a maximum of 12 months. The randomisation sequence was generated within an interactive web response system (Alea); patients were stratified according to epithelioid versus non-epithelioid histology and were assigned in random block sizes of 3 and 6. Participants and treating clinicians were masked to group allocation. The co-primary endpoints were investigator-assessed progression-free survival and overall survival, analysed according to the treatment policy estimand (an equivalent of the intention-to-treat principle). All patients who were randomly assigned were included in the safety population, reported according to group allocation. This trial is registered with Clinicaltrials.gov, NCT03063450. FINDINGS: Between May 10, 2017, and March 30, 2020, 332 patients were recruited, of whom 221 (67%) were randomly assigned to the nivolumab group and 111 (33%) were assigned to the placebo group). Median follow-up was 11·6 months (IQR 7·2-16·8). Median progression-free survival was 3·0 months (95% CI 2·8-4·1) in the nivolumab group versus 1·8 months (1·4-2·6) in the placebo group (adjusted hazard ratio [HR] 0·67 [95% CI 0·53-0·85; p=0·0012). Median overall survival was 10·2 months (95% CI 8·5-12·1) in the nivolumab group versus 6·9 months (5·0-8·0) in the placebo group (adjusted HR 0·69 [95% CI 0·52-0·91]; p=0·0090). The most frequently reported grade 3 or worse treatment-related adverse events were diarrhoea (six [3%] of 221 in the nivolumab group vs two [2%] of 111 in the placebo group) and infusion-related reaction (six [3%] vs none). Serious adverse events occurred in 90 (41%) patients in the nivolumab group and 49 (44%) patients in the placebo group. There were no treatment-related deaths in either group. INTERPRETATION: Nivolumab represents a treatment that might be beneficial to patients with malignant mesothelioma who have progressed on first-line therapy. FUNDING: Stand up to Cancer-Cancer Research UK and Bristol Myers Squibb.

Optimal dose and safety of molnupiravir in patients with early SARS-CoV-2: a Phase I, open-label, dose-escalating, randomized controlled study.

OBJECTIVES: AGILE is a Phase Ib/IIa platform for rapidly evaluating COVID-19 treatments. In this trial (NCT04746183) we evaluated the safety and optimal dose of molnupiravir in participants with early symptomatic infection. METHODS: We undertook a dose-escalating, open-label, randomized-controlled (standard-of-care) Bayesian adaptive Phase I trial at the Royal Liverpool and Broadgreen Clinical Research Facility. Participants (adult outpatients with PCR-confirmed SARS-CoV-2 infection within 5 days of symptom onset) were randomized 2:1 in groups of 6 participants to 300, 600 and 800 mg doses of molnupiravir orally, twice daily for 5 days or control. A dose was judged unsafe if the probability of 30% or greater dose-limiting toxicity (the primary outcome) over controls was 25% or greater. Secondary outcomes included safety, clinical progression, pharmacokinetics and virological responses. RESULTS: Of 103 participants screened, 18 participants were enrolled between 17 July and 30 October 2020. Molnupiravir was well tolerated at 300, 600 and 800 mg doses with no serious or severe adverse events. Overall, 4 of 4 (100%), 4 of 4 (100%) and 1 of 4 (25%) of the participants receiving 300, 600 and 800 mg molnupiravir, respectively, and 5 of 6 (83%) controls, had at least one adverse event, all of which were mild (≤grade 2). The probability of ≥30% excess toxicity over controls at 800 mg was estimated at 0.9%. CONCLUSIONS: Molnupiravir was safe and well tolerated; a dose of 800 mg twice daily for 5 days was recommended for Phase II evaluation.

The effect of time spent in rehabilitation on activity limitation and impairment after stroke.

BACKGROUND: Stroke affects millions of people every year and is a leading cause of disability, resulting in significant financial cost and reduction in quality of life. Rehabilitation after stroke aims to reduce disability by facilitating recovery of impairment, activity, or participation. One aspect of stroke rehabilitation that may affect outcomes is the amount of time spent in rehabilitation, including minutes provided, frequency (i.e. days per week of rehabilitation), and duration (i.e. time period over which rehabilitation is provided). Effect of time spent in rehabilitation after stroke has been explored extensively in the literature, but findings are inconsistent. Previous systematic reviews with meta-analyses have included studies that differ not only in the amount provided, but also type of rehabilitation. OBJECTIVES: To assess the effect of 1. more time spent in the same type of rehabilitation on activity measures in people with stroke; 2. difference in total rehabilitation time (in minutes) on recovery of activity in people with stroke; and 3. rehabilitation schedule on activity in terms of: a. average time (minutes) per week undergoing rehabilitation, b. frequency (number of sessions per week) of rehabilitation, and c. total duration of rehabilitation. SEARCH METHODS: We searched the Cochrane Stroke Group trials register, CENTRAL, MEDLINE, Embase, eight other databases, and five trials registers to June 2021. We searched reference lists of identified studies, contacted key authors, and undertook reference searching using Web of Science Cited Reference Search. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of adults with stroke that compared different amounts of time spent, greater than zero, in rehabilitation (any non-pharmacological, non-surgical intervention aimed to improve activity after stroke). Studies varied only in the amount of time in rehabilitation between experimental and control conditions. Primary outcome was activities of daily living (ADLs); secondary outcomes were activity measures of upper and lower limbs, motor impairment measures of upper and lower limbs, and serious adverse events (SAE)/death. DATA COLLECTION AND ANALYSIS: Two review authors independently screened studies, extracted data, assessed methodological quality using the Cochrane RoB 2 tool, and assessed certainty of the evidence using GRADE. For continuous outcomes using different scales, we calculated pooled standardised mean difference (SMDs) and 95% confidence intervals (CIs). We expressed dichotomous outcomes as risk ratios (RR) with 95% CIs. MAIN RESULTS: The quantitative synthesis of this review comprised 21 parallel RCTs, involving analysed data from 1412 participants.  Time in rehabilitation varied between studies. Minutes provided per week were 90 to 1288. Days per week of rehabilitation were three to seven. Duration of rehabilitation was two weeks to six months. Thirteen studies provided upper limb rehabilitation, five general rehabilitation, two mobilisation training, and one lower limb training. Sixteen studies examined participants in the first six months following stroke; the remaining five included participants more than six months poststroke. Comparison of stroke severity or level of impairment was limited due to variations in measurement. The risk of bias assessment suggests there were issues with the methodological quality of the included studies. There were 76 outcome-level risk of bias assessments: 15 low risk, 37 some concerns, and 24 high risk. When comparing groups that spent more time versus less time in rehabilitation immediately after intervention, we found no difference in rehabilitation for ADL outcomes (SMD 0.13, 95% CI -0.02 to 0.28; P = 0.09; I2 = 7%; 14 studies, 864 participants; very low-certainty evidence), activity measures of the upper limb (SMD 0.09, 95% CI -0.11 to 0.29; P = 0.36; I2 = 0%; 12 studies, 426 participants; very low-certainty evidence), and activity measures of the lower limb (SMD 0.25, 95% CI -0.03 to 0.53; P = 0.08; I2 = 48%; 5 studies, 425 participants; very low-certainty evidence). We found an effect in favour of more time in rehabilitation for motor impairment measures of the upper limb (SMD 0.32, 95% CI 0.06 to 0.58; P = 0.01; I2 = 10%; 9 studies, 287 participants; low-certainty evidence) and of the lower limb (SMD 0.71, 95% CI 0.15 to 1.28; P = 0.01; 1 study, 51 participants; very low-certainty evidence). There were no intervention-related SAEs. More time in rehabilitation did not affect the risk of SAEs/death (RR 1.20, 95% CI 0.51 to 2.85; P = 0.68; I2 = 0%; 2 studies, 379 participants; low-certainty evidence), but few studies measured these outcomes. Predefined subgroup analyses comparing studies with a larger difference of total time spent in rehabilitation between intervention groups to studies with a smaller difference found greater improvements for studies with a larger difference. This was statistically significant for ADL outcomes (P = 0.02) and activity measures of the upper limb (P = 0.04), but not for activity measures of the lower limb (P = 0.41) or motor impairment measures of the upper limb (P = 0.06). AUTHORS' CONCLUSIONS: An increase in time spent in the same type of rehabilitation after stroke results in little to no difference in meaningful activities such as activities of daily living and activities of the upper and lower limb but a small benefit in measures of motor impairment (low- to very low-certainty evidence for all findings). If the increase in time spent in rehabilitation exceeds a threshold, this may lead to improved outcomes. There is currently insufficient evidence to recommend a minimum beneficial daily amount in clinical practice. The findings of this study are limited by a lack of studies with a significant contrast in amount of additional rehabilitation provided between control and intervention groups. Large, well-designed, high-quality RCTs that measure time spent in all rehabilitation activities (not just interventional) and provide a large contrast (minimum of 1000 minutes) in amount of rehabilitation between groups would provide further evidence for effect of time spent in rehabilitation.

Supporting patient access to medicines in community palliative care: on-line survey of health professionals' practice, perceived effectiveness and influencing factors.

BACKGROUND: Patient access to medicines at home during the last year of life is critical for symptom control, but is thought to be problematic. Little is known about healthcare professionals' practices in supporting timely medicines access and what influences their effectiveness. The purpose of the study was to evaluate health professionals' medicines access practices, perceived effectiveness and influencing factors. METHODS: On-line questionnaire survey of health care professionals (General Practitioners, Community Pharmacists, community-based Clinical Nurse Specialists and Community Nurses) delivering end-of-life care in primary and community care settings in England. Quantitative data were analysed using descriptive statistics. RESULTS: One thousand three hundred twenty-seven responses were received. All health professional groups are engaged in supporting access to prescriptions, using a number of different methods. GPs remain a predominant route for patients to access new prescriptions in working hours. However, nurses and, increasingly, primary care-based pharmacists are also actively contributing. However, only 42% (160) of Clinical Nurse Specialists and 27% (27) of Community Nurses were trained as prescribers. The majority (58% 142) of prescribing nurses and pharmacists did not have access to an electronic prescribing system. Satisfaction with access to shared patient records to facilitate medicines access was low: 39% (507) were either Not At All or only Slightly satisfied. Out-of-hours specialist cover was reported by less than half (49%; 656) and many General Practitioners and pharmacists lacked confidence advising about out-of-hours services. Respondents perceived there would be a significant improvement in pain control if access to medicines was greater. Those with shared records access reported significantly lower pain estimates for their caseload patients. CONCLUSIONS: Action is required to support a greater number of nurses and pharmacists to prescribe end-of-life medicines. Solutions are also required to enable shared access to patient records across health professional groups. Coverage and awareness of out-of-hours services to access medicines needs to be improved.

12-hr shifts in nursing: Do they remove unproductive time and information loss or do they reduce education and discussion opportunities for nurses? A cross-sectional study in 12 European countries.

AIMS AND OBJECTIVES: To examine the association between registered nurses' (referred to as "nurses" for brevity) shifts of 12 hr or more and presence of continuing educational programmes; ability to discuss patient care with other nurses; assignments that foster continuity of care; and patient care information being lost during handovers. BACKGROUND: The introduction of long shifts (i.e., shifts of 12 hr or more) remains controversial. While there are claims of efficiency, studies have shown long shifts to be associated with adverse effects on quality of care. Efficiency claims are predicated on the assumption that long shifts reduce overlaps between shifts; these overlaps are believed to be unproductive and dangerous. However, there are potentially valuable educational and communication activities that occur during these overlaps. DESIGN: Cross-sectional survey of 31,627 nurses within 487 hospitals in 12 European countries. METHODS: The associations were measured through generalised linear mixed models. The study methods were compliant with the STROBE checklist. RESULTS: When nurses worked shifts of 12 hr or more, they were less likely to report having continuing educational programmes; and time to discuss patient care with other nurses, compared to nurses working 8 hr or less. Nurses working shifts of 12 hr or more were less likely to report assignments that foster continuity of care, albeit the association was not significant. Similarly, working long shifts was associated with reports of patient care information being lost during handovers, although association was not significant. CONCLUSION: Working shifts of 12 hr or more is associated with reduced educational activities and fewer opportunities to discuss patient care, with potential negative consequences for safe and effective care. RELEVANCE TO CLINICAL PRACTICE: Implementation of long shifts should be questioned, as reduced opportunity to discuss care or participate in educational activities may jeopardise the quality and safety of care for patients.

Accuracy of nature of call screening tool in identifying patients requiring treatment for out of hospital cardiac arrest.

BACKGROUND: A new pre-triage screening tool, Nature of Call (NoC), has been introduced into the telephone triage system of UK ambulance services which employ National Health Service Pathways (NHSP). Its function is to provide rapid recognition of patients who may need immediate ambulance dispatch for out-of-hospital cardiac arrest (OHCA) and withholding dispatch for other calls while further triage is undertaken. In this study, we evaluated the accuracy of NoC and NHSP in identifying patients with potentially treatable or imminent OHCA. METHODS: This retrospective, observational study reviewed consecutive calls to a UK ambulance service between October 2016 and February 2017 in which NOC, and then NHSP were applied sequentially. Only those calls for which a corresponding electronic Patient Clinical Record was available were included. Sensitivity and specificity of NOC and NHSP for recognition of an OHCA were determined by comparing allocated priority dispositions with an OHCA Treatment Registry (OHCATR). RESULTS: Of 96 423 calls received, 71 373 were reviewed. For 590 (0.8%) of these calls, the patients received treatment for OHCA. NOC identified 458 OHCATR patients; NHSP identified 467; together they identified 496. NoC captured 29 patients not identified by NHSP; NHSP captured 38 patients not identified by NOC. For NOC sensitivity was 77.6% (95% CI 74.1 to 80.8) and specificity 86.9% (95% CI 86.6 to 87.1). NHSP sensitivity was 79.2% (95% CI 75.7 to 82.2) and specificity 93.4% (95% CI 93.2 to 93.6). NoC and NHSP combined had a sensitivity of 84.1% (95% CI 80.9 to 86.8) and specificity of 85.3% (95% CI 85.1 to 85.6). CONCLUSIONS: NoC and NHSP call categorisation each achieved similar sensitivity for the identification of OHCATR, identifying most of the same patients, but each captured unique patients. Using both methods sequentially improved accuracy. The 16% of OHCATR patients not identified by either method present a challenge to ambulance dispatch systems.

Electronic prescribing system design priorities for antimicrobial stewardship: a cross-sectional survey of 142 UK infection specialists.

Background: The implementation of electronic prescribing and medication administration (EPMA) systems is a priority for hospitals and a potential component of antimicrobial stewardship (AMS). Objectives: To identify software features within EPMA systems that could potentially facilitate AMS and to survey practising UK infection specialist healthcare professionals in order to assign priority to these software features. Methods: A questionnaire was developed using nominal group technique and transmitted via email links through professional networks. The questionnaire collected demographic data, information on priority areas and anticipated impact of EPMA. Responses from different respondent groups were compared using the Mann-Whitney U -test. Results: Responses were received from 164 individuals (142 analysable). Respondents were predominantly specialist infection pharmacists (48%) or medical microbiologists (37%). Of the pharmacists, 59% had experience of EPMA in their hospitals compared with 35% of microbiologists. Pharmacists assigned higher priority to indication prompt ( P < 0.001), allergy checker ( P = 0.003), treatment protocols ( P = 0.003), drug-indication mismatch alerts ( P = 0.031) and prolonged course alerts ( P = 0.041) and lower priority to a dose checker for adults ( P = 0.02) and an interaction checker ( P < 0.05) than microbiologists. A 'soft stop' functionality was rated essential or high priority by 89% of respondents. Potential EPMA software features were expected to have the greatest impact on stewardship, treatment efficacy and patient safety outcomes with lowest impact on Clostridium difficile infection, antimicrobial resistance and drug expenditure. Conclusions: The survey demonstrates key differences in health professionals' opinions of potential healthcare benefits of EPMA, but a consensus of anticipated positive impact on patient safety and AMS.

Prevalence of cancer chemotherapy-related problems, their relation to health-related quality of life and associated supportive care: a cross-sectional survey.

PURPOSE: The purpose of this study was to identify the treatment-associated problems that most impact on patients undergoing cancer chemotherapy, how problems relate to experiences of supportive care and variations in experience between cancer treatment centres. METHODS: A survey administered to patients at six cancer centres in England explored variations of prevalence of 17 cancer chemotherapy-associated problems and associated supportive care. Problem items were identified as the most frequently experienced and severe when experienced in a scoping and consensus exercise. A health-related quality of life (HRQoL) measure, the EQ5D, was included to measure impact of problems. RESULTS: A total of 363 completed questionnaires were returned (response rate 43 %, median 61 %). The most prevalent problem was 'tiredness/fatigued' (90 %), followed by 'changes in taste & smell' (69 %) and 'difficulty managing everyday tasks' (61 %). Significant variations in problem prevalence existed between centres, and some common problems were rarely reported in the literature. Regression analysis found that almost all problems were significantly associated with HRQoL, with social/emotional problems having as much impact on HRQoL as physical/psychological side effects of treatment. Greatest effect size was for difficulty managing everyday tasks. Respondents reported significant variations in supportive care between centres, with more supportive care received for physical/psychological problems than for social/emotional problems. Findings indicated that patients who received increased supportive care experienced less severe problems. CONCLUSION: The most common and distressing chemotherapy-associated problems were identified. These problems are mitigated by quality supportive care. Routine measurement and monitoring of problem items and supportive care are warranted to facilitate benchmarking and service improvements both within and between cancer centres.

A web-based intervention (RESTORE) to support self-management of cancer-related fatigue following primary cancer treatment: a multi-centre proof of concept randomised controlled trial.

PURPOSE: Cancer-related fatigue (CRF) is a frequent and distressing symptom experienced after cancer treatment. RESTORE is the first web-based resource designed to enhance self-efficacy to manage CRF following curative-intent treatment. The aim of this study is to test the proof of concept and inform the design of an effectiveness trial. METHODS: A multi-centre parallel-group two-armed (1:1) exploratory randomised controlled trial (RCT) with qualitative process evaluation was employed in the study. Participants (≥18 years; ≤5 years post treatment with moderate to severe fatigue) were recruited and randomly assigned to RESTORE or a leaflet. Feasibility and acceptability were measured by recruitment, attrition, intervention adherence, completion of outcome measures and process evaluation. Change in self-efficacy to manage CRF was also explored. Outcome measures were completed at baseline (T0), 6 weeks (T1) and 12 weeks (T2). Data were analysed using mixed-effects linear regression and directed content analysis. RESULTS: One hundred and sixty-three people participated in the trial and 19 in the process evaluation. The intervention was feasible (39 % of eligible patients consented) and acceptable (attrition rate 36 %). There was evidence of higher fatigue self-efficacy at T1 in the intervention group vs comparator (mean difference 0.51 [-0.08 to 1.11]), though the difference in groups decreased by 12 weeks. Time since diagnosis influenced perceived usefulness of the intervention. Modifications were suggested. CONCLUSION: Proof of concept was achieved. The RESTORE intervention should be subject to a definitive trial with some adjustments. Provision of an effective supportive resource would empower cancer survivors to manage CRF after treatment completion. TRIAL REGISTRATION: ISRCTN67521059.

Intra and inter-rater reliability of screening for movement impairments: movement control tests from the foundation matrix.

Pre-season screening is well established within the sporting arena, and aims to enhance performance and reduce injury risk. With the increasing need to identify potential injury with greater accuracy, a new risk assessment process has been produced; The Performance Matrix (battery of movement control tests). As with any new method of objective testing, it is fundamental to establish whether the same results can be reproduced between examiners and by the same examiner on consecutive occasions. This study aimed to determine the intra-rater test re-test and inter-rater reliability of tests from a component of The Performance Matrix, The Foundation Matrix. Twenty participants were screened by two experienced musculoskeletal therapists using nine tests to assess the ability to control movement during specific tasks. Movement evaluation criteria for each test were rated as pass or fail. The therapists observed participants real-time and tests were recorded on video to enable repeated ratings four months later to examine intra-rater reliability (videos rated two weeks apart). Overall test percentage agreement was 87% for inter-rater reliability; 98% Rater 1, 94% Rater 2 for test re-test reliability; and 75% for real-time versus video. Intraclass-correlation coefficients (ICCs) were excellent between raters (0.81) and within raters (Rater 1, 0.96; Rater 2, 0.88) but poor for real-time versus video (0.23). Reliability for individual components of each test was more variable: inter-rater, 68-100%; intra-rater, 88-100% Rater 1, 75-100% Rater 2; and real-time versus video 31-100%. Cohen's Kappa values for inter-rater reliability were 0.0-1.0; intra-rater 0.6-1.0 for Rater 1; -0.1-1.0 for Rater 2; and -0.1-1 for real-time versus video. It is concluded that both inter and intra-rater reliability of tests in The Foundation Matrix are acceptable when rated by experienced therapists. Recommendations are made for modifying some of the criteria to improve reliability where excellence was not reached. Key pointsThe movement control tests of The Foundation Matrix had acceptable reliability between raters and within raters on different daysAgreement between observations made on tests performed real-time and on video recordings was low, indicating poor validity of use of video recordingsSome movement evaluation criteria related to specific tests that did not achieve excellent agreement could be modified to improve reliability.

Principles into Practice: An Observational Study of Physiotherapists use of Motor Learning Principles in Stroke Rehabilitation.

OBJECTIVE(S): To describe a) how motor learning principles are applied during post stroke physiotherapy, with a focus on lower limb rehabilitation; and b) the context in which these principles are used, in relation to patient and/or task characteristics. DESIGN: Direct non-participation observation of routine physiotherapy sessions, with data collected via video recording. A structured analysis matrix and pre-agreed definitions were used to identify, count and record: type of activity; repetitions; instructional and feedback statements (frequency and type); strategies such as observational learning and augmented feedback. Data was visualised using scatter plots, and analysed descriptively. SETTING: 6 UK Stroke Units PARTICIPANTS: 89 therapy sessions were observed, involving 55 clinicians and 57 patients. RESULTS: Proportion of time spent active within each session ranged from 26% to 98% (mean 85, SD 19). The frequency of task repetition varied widely, with a median of 3.7 repetitions per minute (IQR 2.1-8.6). Coaching statements were common (mean 6.46 per minute), with 52% categorised as instructions, 14% as feedback, and 34% as verbal cues/motivational statements. 13% of instructions and 6% of feedback statements were externally focussed. Examining the use of different coaching behaviours in relation to patient characteristics found no associations. Overall, practice varied widely across the dataset. CONCLUSIONS: To optimise the potential for motor skill learning, therapists must manipulate features of their coaching language (what they say, how much and when) and practice design (type, number, difficulty and variability of task). There is an opportunity to implement motor learning principles more consistently, to benefit motor skill recovery following stroke. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov (NCT03792126). CONTRIBUTION OF THE PAPER.

Evaluating niraparib versus active symptom control in patients with previously treated mesothelioma (NERO): a study protocol for a multicentre, randomised, two-arm, open-label phase II trial in UK secondary care centres.

BACKGROUND: Malignant mesothelioma is a rapidly lethal cancer that has been increasing at an epidemic rate over the last three decades. Targeted therapies for mesothelioma have been lacking. A previous study called MiST1 (NCT03654833), evaluated the efficacy of Poly (ADP-ribose) polymerase (PARP) inhibition in mesothelioma. This study met its primary endpoint with 15% of patients having durable responses exceeding 1 year. Therefore, there is a need to evaluate PARP inhibitors in relapsed mesothelioma patients, where options are limited. Niraparib is the PARP inhibitor used in NERO. METHODS: NERO is a multicentre, two-arm, open-label UK randomised phase II trial designed to evaluate the efficacy of PARP inhibition in relapsed mesothelioma. 84 patients are being recruited. NERO is not restricted by line of therapy; however, eligible participants must have been treated with an approved platinum based systemic therapy. Participants will be randomised 2:1, stratified according to histology and response to prior platinum-based chemotherapy, to receive either active symptom control (ASC) and niraparib or ASC alone, for up to 24 weeks. Participants will be treated until disease progression, withdrawal, death or development of significant treatment limiting toxicity. Participants randomised to niraparib will receive 200 or 300 mg daily in a 3-weekly cycle. The primary endpoint is progression-free survival, where progression is determined by modified Response Evaluation Criteria in Solid Tumors (mRECIST) or RECIST 1.1; investigator reported progression; or death from any cause, whichever comes first. Secondary endpoints include overall survival, best overall response, 12-week and 24 week disease control, duration of response, treatment compliance and safety/tolerability. If NERO shows niraparib to be safe and biologically effective, it may lead to future late phase randomised controlled trials in relapsed mesothelioma. ETHICS AND DISSEMINATION: The study received ethical approval from London-Hampstead Research Ethics Committee on 06-May-2022 (22/LO/0281). Data from all centres will be analysed together and published as soon as possible. TRIAL REGISTRATION NUMBER: ISCRTN16171129; NCT05455424.

Molnupiravir versus placebo in unvaccinated and vaccinated patients with early SARS-CoV-2 infection in the UK (AGILE CST-2): a randomised, placebo-controlled, double-blind, phase 2 trial.

BACKGROUND: The antiviral drug molnupiravir was licensed for treating at-risk patients with COVID-19 on the basis of data from unvaccinated adults. We aimed to evaluate the safety and virological efficacy of molnupiravir in vaccinated and unvaccinated individuals with COVID-19. METHODS: This randomised, placebo-controlled, double-blind, phase 2 trial (AGILE CST-2) was done at five National Institute for Health and Care Research sites in the UK. Eligible participants were adult (aged ≥18 years) outpatients with PCR-confirmed, mild-to-moderate SARS-CoV-2 infection who were within 5 days of symptom onset. Using permuted blocks (block size 2 or 4) and stratifying by site, participants were randomly assigned (1:1) to receive either molnupiravir (orally; 800 mg twice daily for 5 days) plus standard of care or matching placebo plus standard of care. The primary outcome was the time from randomisation to SARS-CoV-2 PCR negativity on nasopharyngeal swabs and was analysed by use of a Bayesian Cox proportional hazards model for estimating the probability of a superior virological response (hazard ratio [HR]>1) for molnupiravir versus placebo. Our primary model used a two-point prior based on equal prior probabilities (50%) that the HR was 1·0 or 1·5. We defined a priori that if the probability of a HR of more than 1 was more than 80% molnupiravir would be recommended for further testing. The primary outcome was analysed in the intention-to-treat population and safety was analysed in the safety population, comprising participants who had received at least one dose of allocated treatment. This trial is registered in ClinicalTrials.gov, NCT04746183, and the ISRCTN registry, ISRCTN27106947, and is ongoing. FINDINGS: Between Nov 18, 2020, and March 16, 2022, 1723 patients were assessed for eligibility, of whom 180 were randomly assigned to receive either molnupiravir (n=90) or placebo (n=90) and were included in the intention-to-treat analysis. 103 (57%) of 180 participants were female and 77 (43%) were male and 90 (50%) participants had received at least one dose of a COVID-19 vaccine. SARS-CoV-2 infections with the delta (B.1.617.2; 72 [40%] of 180), alpha (B.1.1.7; 37 [21%]), omicron (B.1.1.529; 38 [21%]), and EU1 (B.1.177; 28 [16%]) variants were represented. All 180 participants received at least one dose of treatment and four participants discontinued the study (one in the molnupiravir group and three in the placebo group). Participants in the molnupiravir group had a faster median time from randomisation to negative PCR (8 days [95% CI 8-9]) than participants in the placebo group (11 days [10-11]; HR 1·30, 95% credible interval 0·92-1·71; log-rank p=0·074). The probability of molnupiravir being superior to placebo (HR>1) was 75·4%, which was less than our threshold of 80%. 73 (81%) of 90 participants in the molnupiravir group and 68 (76%) of 90 participants in the placebo group had at least one adverse event by day 29. One participant in the molnupiravir group and three participants in the placebo group had an adverse event of a Common Terminology Criteria for Adverse Events grade 3 or higher severity. No participants died (due to any cause) during the trial. INTERPRETATION: We found molnupiravir to be well tolerated and, although our predefined threshold was not reached, we observed some evidence that molnupiravir has antiviral activity in vaccinated and unvaccinated individuals infected with a broad range of SARS-CoV-2 variants, although this evidence is not conclusive. FUNDING: Ridgeback Biotherapeutics, the UK National Institute for Health and Care Research, the Medical Research Council, and the Wellcome Trust.